HIV patients demonstrate changes in fat distribution, impaired glucose homeostasis, and increased CV risk. Increased traditional CV risk markers, including dyslipidemia, insulin resistance, hypertension and central adiposity, as well as increased inflammatory indices, may all contribute to increased MI rates in HIV patients. Novel preliminary data presented in this grant proposal suggest that the renin-angiotensin-aldosterone (RAA) may be dysregulated in HIV patients, in association with excess visceral adiposity (VAT), and may contribute to a number of the metabolic abnormalities, including glucose dysregulation, in this population. In the revised proposal, we will carefully investigate the RAA axis, which has yet to be fully investigated in this population. Preliminary data from our group demonstrate increased urinary aldosterone in HIV- patients compared to controls, with aldosterone independently and positively associated with both VAT and with abnormal glucose as measured by HbA1c. Data from animal and human studies demonstrate associations between aldosterone, adipose tissue mass, insulin sensitivity, and systemic and vascular inflammation, suggesting that increased aldosterone in HIV may exacerbate CV risk. In Aim I of the current proposal, we will characterize aldosterone levels and aldosterone response to angiotensin II infusion in both HIV- and non-HIV infected subjects, to determine the independent contributions of HIV-infection itself and VAT to aldosterone levels. We will further determine the relationship between aldosterone concentrations and fat distribution including ectopic accumulation of fat in the liver and muscle using MR-spectroscopy, endothelial function assessed by flow-mediated dilation, insulin sensitivity and inflammatory adipokines and investigate the relationship between perturbations in the RAA and other endocrine axes in HIV, including GH, adrenal and gonadal. In Aim II of this proposal, we will test the efficacy of a selective mineralocorticoid receptor (MR blocker, eplerenone, to improve insulin sensitivity and CV risk parameters in HIV patients with impaired glucose tolerance and increased VAT. Our group has previously investigated the efficacy of lifestyle modification (LSM) in this population, demonstrating that LSM improves some measures of body composition and CV risk, but does not reverse all of the cardiometabolic abnormalities in this population. In the current proposal, on a background of LSM for all subjects, we will perform a double-blind, placebo-controlled study of eplerenone treatment for six months, followed by a six month open label extension phase, to test the effects of MR blockade on insulin stimulated glucose uptake, ectopic fat distribution, systemic markers of inflammation, endothelial function and other endocrine systems. We hypothesize that aldosterone levels are increased in HIV-infection and that MR blockade with eplerenone added to LSM will improve insulin sensitivity, decrease markers of systemic inflammation, and improve endothelial function. If successful, this proposal will demonstrate a much-needed physiologically-based strategy for treating cardiometabolic abnormalities in HIV. PUBLIC HEALTH RELEVANCE: In this proposal, we will carefully study the regulation of a hormone called aldosterone in HIV-infection. Aldosterone may be increased in HIV-infection and may contribute to problems with sugar metabolism and increased risk of cardiovascular disease. We will also test whether eplerenone, a drug that decreases the body's response to aldosterone, may improve blood sugar and decrease risks for cardiovascular disease in HIV-infected patients with increased belly fat.